The development of effective drug delivery vehicles continues to present a challenge for drug manufacturers. Many bioactive agents, while displaying potent in vivo activity, are hampered by drawbacks such as in vivo degradation, rapid elimination from the body, low aqueous solubility, and systemic toxicity. Several approaches have been suggested to overcome these drawbacks. Such approaches include, for example, co-administering a bioactive agent with a surfactant, providing the bioactive agent in a liposomal formulation, providing targeting to a specific tissue by employing an antibody, and formulating the bioactive agent within a micelle. Each approach, however, does not fully address the problems encountered with the specific active agent and/or generates additional challenges.
Pharmaceutical grade surfactants, such as Tween 80 or Cremophor®, have been widely used in formulations to compensate for the low aqueous solubility of hydrophobic drugs. These surfactants solubilize hydrophobic drugs by forming micellar structures in aqueous media. Unfortunately, these surfactants have been associated with severe allergic reactions and hypersensitivity when administered to patients (Kris et al. (1986) Cancer Treatment REP 70:5. In addition, micellar drug carriers often disintegrate upon administration to a patient because the concentration of the component forming the micelle falls below its critical micelle concentration (CMC). Once the micelle disintegrates, there is a rapid and uncontrolled release of the drug, thereby often rendering this approach to drug delivery as impracticable.
Liposomal formulations are made up of phospholipids that form liposomes. Upon administration to a patient, the liposomes are taken up by macrophages of the reticulo-endothelial system (“RES”). High levels are often found in the liver and spleen, even when the liposomes are modified to possess “stealth” characteristics by coating them with poly(ethylene glycol) (“PEG”). Even PEG-coated “stealth” liposomes, however, possess undesirable side effects. In particular, such PEG-coated liposomes are known to indiscriminately move from the blood vessels into tissues, a process known as “extravasation.” As a result, higher doses of liposome-encapsulated drug must be administered to achieve a desired therapeutic effect.
Targeted delivery approaches, e.g., using antibodies to deliver drugs such as anticancer agents, have been employed for localized treatment of diseases such as cancer. Unfortunately, the receptors being targeting on the tumor cells are often present on healthy cells as well. Thus, antibody-targeting approaches often lack the specificity or selectivity necessary for providing an optimized method for delivering a bioactive agent.
Still other approaches have been suggested for delivering drugs. For example, water-soluble polymers such as poly(ethylene glycol) have been covalently attached to drugs to form polymer-drug conjugates. Such conjugates often possess improved water solubility, enhanced in vivo stability, and an improved therapeutic index in comparison to the unconjugated or native drug. Unfortunately, monofunctional PEGs, such as monomethoxy-PEG, can carry only one drug molecule per polymer chain, thereby lacking the high drug-carrying capability often sought in delivering bioactive agents.
Thus, there remains a need in the art for improved methods for delivering both hydrophilic and hydrophobic drugs in a therapeutically effective manner. That is to say, there is a need for compositions and methods of drug delivery that are flexible enough to be useful for delivering not only water-insoluble drugs, but are adaptable for use in delivering hydrophilic and charge-bearing bioactive agents as well. The present invention seeks to solve these and other needs in the art.